WO2025070456A1 - Method for producing highly-pure branched polyethylene glycol compound - Google Patents

Abstract

The present invention provides a method for producing a highly-pure branched PEG compound, the method comprising: a step (1a) for mixing, in the presence of a solvent, a porous metal complex with a mixture containing a branched PEG compound and, as an impurity, a linear PEG compound to adsorb the linear PEG compound on the porous metal complex; a step (2a) for removing the porous metal complex having adsorbed the linear PEG compound from the mixture containing the branched PEG compound and the porous metal complex having adsorbed the linear PEG compound to obtain a solution containing the branched PEG compound; and a step (3) for recovering the branched PEG compound from the solution containing the branched PEG compound.

Description

Method for producing high purity branched polyethylene glycol compound

The present invention relates to a method for producing a high-purity branched polyethylene glycol compound.

Polyethylene glycol compounds are widely used as materials for drug delivery systems and medical hydrogels. Medical polyethylene glycol compounds like these are required to have low impurity content.

For example, monomethoxypolyethylene glycol, a type of polyethylene glycol compound, is known to contain, as an impurity, a linear polyethylene glycol having hydroxyl groups at both ends (hereinafter sometimes referred to as a "diol form") that is produced by the reaction of water molecules with ethylene oxide (see, for example, Patent Document 1).

Since diols are produced even when there is a very small amount of moisture in the system during the production of polyethylene glycol compounds, it is difficult to completely suppress their production. For this reason, there is a strong demand for a method to reduce the amount of diols in polyethylene glycol compounds.

On the other hand, a method using a porous metal complex is known as a method for separating multiple polymer compounds from each other (see, for example, Patent Document 2). In the method described in Patent Document 2, multiple polymer compounds are mixed with a porous metal complex, the porous metal complex is filtered, and a specific polymer material present in the pores of the porous metal complex is recovered, thereby concentrating or separating the target polymer compound. In addition, it is known that porous metal complexes such as metal organic frameworks (MOFs) can separate and store gases (see, for example, Patent Document 3).

Japanese Patent Application Publication No. 11-335460 International Publication No. 2019/078171 Special table 2017-500204 publication

The method described in Patent Document 2 separates multiple polymer compounds from one another based on differences in terminal functional groups. However, Patent Document 2 does not disclose the separation of branched polyethylene glycol compounds and linear polyethylene glycol compounds by utilizing differences in branched or linear structures.

The present invention has been made in light of the above-mentioned circumstances, and aims to obtain a high-purity branched polyethylene glycol compound with a reduced content of linear polyethylene glycol compounds (e.g., the above-mentioned diol form) as impurities.

As a result of intensive research, the present inventors have found that by using a porous metal complex, it is possible to remove linear polyethylene glycol compounds from a mixture containing branched polyethylene glycol compounds and linear polyethylene glycol compounds as impurities, thereby obtaining branched polyethylene glycol compounds of high purity. The present invention, based on this finding, is as follows.

[1] A method for producing a high-purity branched polyethylene glycol compound, comprising the steps of:
a step (1a) of mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the presence of a solvent to adsorb the linear polyethylene glycol compound onto the porous metal complex;
a step (2a) of removing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon from a mixture containing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon and the branched polyethylene glycol compound to obtain a solution containing the branched polyethylene glycol compound; and a step (3) of recovering the branched polyethylene glycol compound from the solution containing the branched polyethylene glycol compound.
A manufacturing method comprising:

[2] A method for producing a high-purity branched polyethylene glycol compound, comprising the steps of:
a step (1b) of mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the absence of a solvent to adsorb the linear polyethylene glycol compound onto the porous metal complex;
a step (2b) of mixing a mixture containing a porous metal complex having adsorbed thereon a linear polyethylene glycol compound and a branched polyethylene glycol compound with a solvent, and removing the porous metal complex having adsorbed thereon the linear polyethylene glycol compound from the mixture thus obtained to obtain a solution containing the branched polyethylene glycol compound; and a step (3) of recovering the branched polyethylene glycol compound from the solution containing the branched polyethylene glycol compound.
A manufacturing method comprising:

[3] A method for producing a high-purity branched polyethylene glycol compound, comprising the steps of:
(1) a step of mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the presence or absence of a solvent to adsorb the linear polyethylene glycol compound onto the porous metal complex;
When the mixing in step (1) is carried out in the presence of a solvent, a step (2a) of removing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon from a mixture containing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon and the branched polyethylene glycol compound to obtain a solution containing the branched polyethylene glycol compound; or when the mixing in step (1) is carried out in the absence of a solvent, a step (2b) of mixing the mixture containing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon and the branched polyethylene glycol compound with a solvent, removing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon from the mixture thus obtained to obtain a solution containing the branched polyethylene glycol compound; and a step (3) of recovering the branched polyethylene glycol compound from the solution containing the branched polyethylene glycol compound.
A manufacturing method comprising:

[4] A branched polyethylene glycol compound represented by formula (I):

(In the formula, m is 0 or 1,
When m is 0, s is an integer from 3 to 9, and when m is 1, s is an integer from 2 to 8;
Each of the s n's is independently a number from 20 to 2000;
Y and the s number of X's are each independently a hydroxy group which may be substituted with a substituent, and E is a linker having a valency of (s+m).
The method according to any one of the above [1] to [3], wherein the branched compound is represented by the formula:

[5] The method according to the above [4], wherein the substituent is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an isoheptyl group, a phenyl group, a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.
[6] The method according to the above [4] or [5], wherein E is a linker having a structure obtained by removing a hydroxy group from glycerin, diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, pentaerythritol, dipentaerythritol, tetritol, pentitol, or hexitol.

[7] The method according to any one of [1] to [6] above, wherein the solvent used in step (1a) or step (2b) is at least one selected from the group consisting of N,N-dimethylformamide, ethanol, ethyl acetate, chloroform, and toluene.

[8] The method according to any one of the above [1] to [7], wherein the branched polyethylene glycol compound has a number average molecular weight of 4,000 to 80,000.
[9] The method according to any one of the above [1] to [7], wherein the branched polyethylene glycol compound has a number average molecular weight of 5,000 to 80,000.

[10] The method according to any one of the above [1] to [9], wherein the linear polyethylene glycol compound has a number average molecular weight of 1,500 to 90,000.
[11] The method according to any one of the above [1] to [9], wherein the number average molecular weight of the linear polyethylene glycol compound is 2,000 to 90,000.

According to the present invention, it is possible to remove linear polyethylene glycol compounds from a mixture containing branched polyethylene glycol compounds and linear polyethylene glycol compounds as impurities, thereby obtaining a branched polyethylene glycol compound of high purity.

The present invention will be described below in order. Note that the descriptions in this specification can be combined with each other unless it is clear that they cannot be combined.

The present invention is a method for producing a high-purity branched polyethylene glycol compound. More specifically, the present invention is a method for producing a high-purity branched polyethylene glycol compound by removing a linear polyethylene glycol compound from a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity. Therefore, more precisely, the "high-purity branched polyethylene glycol compound" in the present invention means a mixture containing the branched polyethylene glycol compound (purity: less than 100%) in which the purity of the branched polyethylene glycol compound is improved compared to the mixture containing the branched polyethylene glycol compound and the linear polyethylene glycol compound used in the present invention, or the branched polyethylene glycol compound itself (purity: 100%).

In the present invention, the "purity" of a "high purity branched polyethylene glycol compound" means "100 x mass of the branched polyethylene glycol compound/mass of the entire mixture containing the branched polyethylene glycol compound." When the purity is 100%, the "mixture containing the branched polyethylene glycol compound" in the above formula is the branched polyethylene glycol compound.

In the present invention, the "purity" of the "branched polyethylene glycol compound" is preferably 90% or more, more preferably 92% or more, and even more preferably 95% or more. The upper limit of this purity is 100%.

(Polyethylene glycol compound)
In the present invention, the term "branched polyethylene glycol compound" means a compound which has two or more polyethylene glycol chains and has a branched structure.

In the present invention, a "linear polyethylene glycol compound" refers to a compound that has a polyethylene glycol chain and a linear structure. The "linear polyethylene glycol compound" may have only one polyethylene glycol chain, or may have two or more polyethylene glycol chains (for example, a compound having a linear structure in which two linear polyethylene glycol chains are linked by one linker). A "linear polyethylene glycol compound" is preferably a compound that has one polyethylene glycol chain and a linear structure (for example, the diol form described above).

The number average molecular weight (hereinafter sometimes abbreviated as "Mn") of the branched polyethylene glycol compound is preferably 4,000 or more, more preferably 5,000 or more, even more preferably 20,000 or more, from the viewpoint of separation of the branched polyethylene glycol compound and the linear polyethylene glycol compound (hereinafter sometimes abbreviated as "separation viewpoint"), and is preferably 90,000 or less, more preferably 80,000 or less.

From the viewpoint of separation, the Mn of the linear polyethylene glycol compound is preferably 1,500 or more, more preferably 2,000 or more, even more preferably 10,000 or more, particularly preferably 20,000 or more, and is preferably 90,000 or less, more preferably 80,000 or less, and even more preferably 40,000 or less.

The Mn of the polyethylene glycol compound can be calculated by gel permeation chromatography (GPC) measurement (standard: polyethylene glycol (HO-(C ₂ H ₅ O) _n -H)).

The mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound can be obtained by a known method for producing a branched polyethylene glycol compound.

Examples of methods for producing a branched polyethylene glycol compound include
(i) A method in which a polyhydric alcohol having three or more hydroxy groups is used as a starting material and ethylene oxide is added thereto (see, for example, JP-A-2004-197077);
(ii) A method of reacting a linear polyethylene glycol compound having a hydroxy group with a compound having three or more functional groups capable of reacting with a hydroxy group (see, for example, JP-A-9-504299).
In the above method (i), if water is present during the addition of ethylene oxide, a linear polyethylene glycol having hydroxy groups at both ends is formed as a by-product. In the above method (ii), the raw material linear polyethylene glycol compound may remain as an impurity.

The branched polyethylene glycol compound is preferably represented by formula (I):

(In the formula, m is 0 or 1,
When m is 0, s is an integer from 3 to 9, and when m is 1, s is an integer from 2 to 8;
Each of the s n's is independently a number from 20 to 2000;
Y and the s number of X's are each independently a hydroxy group which may be substituted with a substituent, and E is a linker having a valency of (s+m).
The branched-chain compound is represented by the formula (I) (hereinafter, may be abbreviated as "compound (I)"). Here, "branched-chain compound" means a compound having a branched-chain structure. Therefore, compound (I) specifically means a compound represented by the formula (I) and having a branched-chain structure.

The symbols in formula (I) will be explained below in order.
When m in formula (I) is 0, it means that Y in formula (I) does not exist.
In formula (I), n is the number of repeating oxyethylene units. This number of repeating units is an average value and may be a decimal number.

In formula (I), when m is 0, s is an integer from 3 to 9, preferably an integer from 3 to 5. In formula (I), when m is 1, s is an integer from 2 to 8, preferably an integer from 2 to 4. Therefore, there are multiple n's and multiple X's in formula (I). The s n's may be the same as or different from each other. Similarly, the s X's may be the same as or different from each other.

The s n's in formula (I) are each independently a number from 20 to 2000, preferably a number from 200 to 1000. From the standpoint of ease of production of compound (I), it is preferable that the s n's are the same.

In formula (I), Y and the s Xs are each independently a hydroxy group which may be substituted with a substituent. From the viewpoint of ease of production of compound (I), it is preferable that the s Xs are the same as each other.

In the present invention, a "hydroxy group which may be substituted with a substituent" refers to a hydroxy group or a hydroxy group substituted with a substituent, and a "hydroxy group substituted with a substituent" refers to a hydroxy group (-OR) in which the hydrogen atom (H) of the hydroxy group (-OH) is substituted with a substituent (R).

The substituent of the hydroxy group described above is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an isoheptyl group, a phenyl group, a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, more preferably a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, and even more preferably a benzyl group.

The s X's are
Preferably, each independently represents a hydroxy group optionally substituted with a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an isoheptyl group, a phenyl group, a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group;
More preferably, each independently represents a hydroxy group optionally substituted with a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group,
More preferably, they are both hydroxy groups (that is, unsubstituted hydroxy groups).

Y is,
Preferred are hydroxy groups optionally substituted with a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an isoheptyl group, a phenyl group, a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group;
More preferably, it is a hydroxy group optionally substituted with a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.
More preferably, it is a hydroxy group substituted with a benzyl group.

E in formula (I) is an (s+m)-valent linker, i.e., a trivalent to nonavalent linker. E is preferably a linker having a structure obtained by removing a hydroxy group from glycerin, diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, pentaerythritol, dipentaerythritol, tetritol, pentitol, or hexitol.

The above diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, and heptaglycerin are compounds generally collectively referred to as "polyglycerin (also known as polyglycerol)." "Polyglycerin" refers to a compound having a structure in which multiple glycerins (also known as glycerols) are bonded together through ether bonds. Specifically, "diglycerin" refers to a compound having a structure in which two glycerins are bonded together through ether bonds, and "heptaglycerin" refers to a compound having a structure in which seven glycerins are bonded together through ether bonds. "Triglycerin," "tetraglycerin," "pentaglycerin," and "hexaglycerin" also have the same meaning as "diglycerin" and "heptaglycerin." Polyglycerol may have a structure in which multiple glycerols are bonded in a linear chain, or may have a structure in which multiple glycerols are bonded in a branched chain.

In the present invention, "tetritol" refers to a tetrahydric sugar alcohol represented by the formula: C ₄ H ₆ (OH) ₄ , and an example thereof is erythritol.
In the present invention, "pentitol" refers to a pentavalent sugar alcohol represented by the formula: C ₅ H ₇ (OH) ₅ , and examples thereof include xylitol.
In the present invention, the term "hexitol" refers to a hexavalent sugar alcohol represented by the formula: C ₆ H ₈ (OH) ₆ , and examples thereof include mannitol.

In formula (I), when m is 0, s is an integer from 3 to 5, when m is 1, s is an integer from 2 to 4, and E is one of formulas (IIa) to (IIc):

(In the formula, * indicates the bond position.)
It is preferable that the linker is represented by any one of the following formulas. Note that * indicates the bond position, not the carbon atom. In other words, "*-" indicates a single bond.

The linker represented by formula (IIa) has a structure obtained by removing a hydroxyl group from glycerin, the linker represented by formula (IIb) has a structure obtained by removing a hydroxyl group from pentaerythritol, and the linker represented by formula (IIc) has a structure obtained by removing a hydroxyl group from a pentitol (e.g., xylitol).

In formula (I), when m is 0, s is an integer of 3 or 4, and when m is 1, s is an integer of 2 or 3, and more preferably, E is a linker represented by formula (IIa) or formula (IIb).

(Porous Metal Complex)
In the present invention, the separation of the branched polyethylene glycol compound and the linear polyethylene glycol compound by the porous metal complex is carried out by adsorption of the linear polyethylene glycol compound to the porous metal complex. Here, the term "porous metal complex" refers to a metal complex having a porous three-dimensional structure formed by a metal ion and an organic bridging ligand connecting the metal ion. Only one type of porous metal complex may be used, or two or more types may be used in combination.

The pore diameter of the porous metal complex is preferably 0.3 nm or more, more preferably 0.4 nm or more, even more preferably 0.5 nm or more, and is preferably 5 nm or less, more preferably 3 nm or less, even more preferably 2 nm or less, and particularly preferably 1.5 nm or less. The pore diameter can be measured by nitrogen gas adsorption, single crystal X-ray diffraction, or powder X-ray diffraction.

Examples of porous metal complexes include the following:
(i) a metal complex having a structure in which polyhedra formed from metal ions and a first organic bridging ligand are three-dimensionally connected and pores are formed between the polyhedra; and (ii) a metal complex having a structure in which two-dimensional sheets formed from metal ions and a first organic bridging ligand are arranged in layers, and adjacent sheets are connected to each other by a second organic bridging ligand capable of bidentate coordination, whereby a pore is formed between the sheets.
The metal complex (i) differs from the metal complex (ii) in that it does not contain a second organic bridging ligand.

The porous metal complexes used in the present invention broadly include porous metal complexes known as MOFs. The pores of the porous metal complexes are preferably linear tunnel-shaped pores.

The metal ion of the porous metal complex may be, for example, an ion of a metal belonging to Groups 1 to 13 of the periodic table. Examples of the metal include zinc, copper, aluminum, gold, platinum, silver, ruthenium, tin, palladium, rhodium, iridium, osmium, nickel, cobalt, iron, yttrium, magnesium, manganese, titanium, zirconium, hafnium, calcium, cadmium, vanadium, chromium, molybdenum, and scandium. The metal ion is preferably an ion of a metal belonging to Groups 6 to 13, more preferably a zinc ion, copper ion, or aluminum ion, and even more preferably a zinc ion.

Examples of the first organic bridging ligand of the porous metal complex include:
(i) Compounds in which two, three or four carboxy groups are bonded to an aromatic compound such as benzene, naphthalene, anthracene, phenanthrene, fluorene, indane, indene, pyrene, 1,4-dihydronaphthalene, tetralin, biphenylene, triphenylene, acenaphthylene, acenaphthene, etc. (These compounds are not limited to halogen atoms (e.g., F, Cl, Br, I), nitro groups, amino groups, acylamino groups (e.g., acetylamino groups), cyano groups, hydroxy groups, methylenedioxy groups (-O-CH ₂ -O-), ethylenedioxy groups (-O-CH ₂ CH ₂ an anion of a linear or branched alkoxy group having 1 to 4 carbon atoms (e.g., a methoxy group, an ethoxy group), a linear or branched alkyl group having 1 to 4 carbon atoms (e.g., a methyl group, an ethyl group, a propyl group, a tert-butyl group, an isobutyl group), -SH, a trifluoromethyl group, a sulfo group, a carbamoyl group, an alkylamino group (e.g., a methylamino group), and a dialkylamino group (e.g., a dimethylamino group), which may be substituted with 1 to 3 substituents selected from the group consisting of
(ii) anion of a cyclic saturated aliphatic polycarboxylic acid having 5 to 12 carbon atoms (e.g., 1,2-cis-cyclopropanedicarboxylic acid, 1,2-trans-cyclopropanedicarboxylic acid, 1,3-cis-cyclobutanedicarboxylic acid, 1,3-trans-cyclobutanedicarboxylic acid, 1,4-cis-cyclohexanedicarboxylic acid, 1,4-trans-cyclohexanedicarboxylic acid, 1,3-adamantanedicarboxylic acid),
(iii) Anions of unsaturated dicarboxylic acids (for example, (1α,2α,4α)-1,2,4-cyclohexanetricarboxylic acid, fumaric acid, maleic acid, citraconic acid, and itaconic acid).

The first organic bridging ligand is preferably an isophthalic acid ion, a 5-methoxyisophthalic acid ion, a 5-methylisophthalic acid ion, a 5-fluoroisophthalic acid ion, a 5-chloroisophthalic acid ion, a 5-bromoisophthalic acid ion, a 5-iodoisophthalic acid ion, a 5-nitroisophthalic acid ion, a 5-cyanoisophthalic acid ion, a terephthalic acid ion, a 2-methylterephthalic acid ion, a 2-methoxyterephthalic acid ion, a 2-nitroterephthalic acid ion, a dihydrocyclobuta[1,2-b]terephthalic acid ion, a 4,4'-dicarboxydiphenylsulfone, a 1,4-naphthalenedicarboxylate ion, a 2,6 ... Examples of the cations include ethane dicarboxylate ion, 9,10-anthracene dicarboxylate ion, 2,3-pyrazine dicarboxylate ion, tetrafluoroterephthalate ion, 4,4'-bibenzoate ion, octafluoro-4,4'-bibenzoate ion, 4,4'-biphenyl dicarboxylate ion, 2,7-fluorenedicarboxylate ion, 2,7-pyrene dicarboxylate ion, 4,5,9,10-tetrahydropyrene-2,7-dicarboxylate ion, succinate ion, maleate ion, fumarate ion, and acetylenedicarboxylate, and more preferably terephthalate ion or 1,4-naphthalenedicarboxylate ion.

The porous metal complex may include a monodentate ligand (e.g., O ²⁻ , H ₂ O, OH ⁻ , OF ⁻ , F ⁻ ) along with a first organic bridging ligand. The use of monodentate ligands allows for control of the crystal size of the complex.

As the monodentate ligand, a monodentate organic ligand may be used. Examples of the monodentate organic ligand include monocarboxylate ions. Examples of the monocarboxylate include formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, pyruvic acid, butanoic acid, pentanoic acid, hexanoic acid, and cyclohexane carboxylic acid.

Examples of the second organic bridging ligand of the porous metal complex include pyrazine, trans-1,2-bis(4-pyridyl)ethylene, 1,4-dicyanobenzene, 4,4'-dicyanobiphenyl, 1,2-dicyanoethylene, 1,4-bis(4-pyridyl)benzene, triethylenediamine, 4,4'-bipyridine, diazapyrene, 2,5-dimethylpyrazine, 2,2'-dimethyl-4,4'-bipyridine, 1,2-bis(4-pyridyl)ethyne, 1,4-bis(4-pyridyl)butadiyne, 1,4-bis(4-pyridyl)benzene, 3,6-di(4-pyridyl)-1,2,4,5-tetramethylpyrazine, azine, 2,2'-bi-1,6-naphthyridine, phenazine, 2,6-di(4-pyridyl)-benzo[1,2-c:4,5-c']dipyrrole-1,3,5,7(2H,6H)-tetrone, N,N'-di(4-pyridyl)-1,4,5,8-naphthalenetetracarboxydiimide, trans-1,2-bis(4-pyridyl)ethene, 4,4'-azopyridine, 1,2-bis(4-pyridyl)ethane, 4,4'-dipyridyl sulfide, 1,3-bis(4-pyridyl)propane, 1,2-bis(4-pyridyl)-glycol, N-(4-pyridyl)isonicotinamide, etc. Among these, triethylenediamine is preferred.

The porous metal complexes that can be used are those described in known literature (e.g., Angew. Chem. Int. Ed. 2004, 43, 2334-2375; Angew. Chem. Int. Ed. 2008, 47, 2-14; Chem. Soc. Rev., 2008, 37, 191-214; PNAS, 2006, 103, 10186-10191; Chem. Rev., 2011, 111, 688-764; Nature, 2003, 423, 705-714).

Examples of porous metal complexes include, but are not limited to, the following: CD-MOF-1, CD-MOF-2, CD-MOF-3, CPM-13, FJI-1, FMOF-1, HKUST-1, IRMOF-1, IRMOF-2, IRMOF-3, IRMOF-6, IRMOF-8, IRMOF-9, IRMOF-13, IRMOF-20, JUC-48, JUC-62, MIL-101, MIL-100, MIL-125, MIL-53, MIL-88 (MIL- 88A, MIL-88B, MIL-88C, MIL-88D series), MOF-5, MOF-74, MOF-177, MOF-210, MOF-200, MOF-205, MOF-505, MOROF-2, MOROF-1, NOT T-100, NOTT-101, NOTT-102, NOTT-103, NOTT-105, NOTT-106, NOTT-107, NOTT-109, NOTT-110, NOTT-111, NOTT-112, NOTT-113, NOTT -114, NOTT-140, NU-100, rho-ZMOF, PCN-6, PCN-6', PCN9, PCN10, PCN12, PCN12', PCN14, PCN16, PCN-17, PCN-21, PCN46, PCN66, PCN6 8, PMOF-2 (Cu), PMOF-3, SNU-5, SNU-15', SNU-21S, SNU-21H, SNU-50, SNU-77H, UiO-66, UiO-67, soc-MOF, sod-ZMOF, TUDMOF-1, UMCM -2, UMCM-150, UTSA-20, ZIF-2, ZIF-3, ZIF-4, ZIF-8, ZIF-9, ZIF- 10, ZIF-11, ZIF-12, ZIF-14, ZIF-20, ZIF-21, ZIF-23, ZIF-60, ZIF -61, ZIF-62, ZIF-64, ZIF-65, ZIF-67, ZIF-68, ZIF-69, ZIF-70, Z IF-71, ZIF-72, ZIF-73, ZIF-74, ZIF-75, ZIF-76, ZIF-77, ZIF-90.

Specific examples of porous metal complexes include the following:
_{Zn 2 (} 1,4-benzenedicarboxylate) ₂ triethylenediamine (pore size = 7.5 Å),
_{Zn 2 (} 1,4-naphthalenedicarboxylate) ₂ triethylenediamine (pore size = 5.7 Å),
IRMOF-1, i.e., Zn ₄ O(BDC) ₃ (BDC=1,4-benzenedicarboxylate, pore size=15.0 Å);
MOF-69C, i.e. Zn ₃ (OH) ₂ (BDC) ₂ (pore size=6.5 Å);
MOF-74, i.e., _M2 (DOBDC) (DOBDC=2,5-dihydroxyterephthalate, M=Zn, Co, Ni, or Mg, pore size=11.0 Å);
HKUST-1, i.e., Cu ₃ (BTC) ₂ (BTC=1,3,5-benzenetricarboxylate, pore size=9.0 Å);
MOF-177, i.e., Zn ₄ O(BTB) ₂ (BTB=4,4',4"-benzene-1,3,5-triyl-tribenzoate, pore size=11.8 Å);
MOF-508, i.e., Zn(BDC)(bpy) _0.5 (bpy=4,4′-bipyridine, pore size=4.0 Å),
Zn-BDC-DABCO, i.e., Zn ₂ (BDC) ₂ (DABCO) (DABCO=(1,4-diazabicyclo[2.2.2]-octane), pore size=7.5 Å);
Cr-MIL-101, i.e., Cr ₃ F(H ₂ O) ₂ O(BDC) ₃ (pore size=29.0 Å);
Al-MIL-110, i.e., Al ₈ (OH) ₁₂ [(OH) ₃ (H ₂ O) ₃ ] (BTC) 3 (pore size = 16.0 Å);
MIL-103, i.e., M(BTB) (M = light rare-earth element = any of La (lanthanum) to Ho (holmium), pore size = 10.7 Å);
Al-MIL-53, i.e., Al(OH)(BDC) (pore size = 8.5 Å);
ZIF-8, i.e., Zn(MeIM) ₂ (MeIM=2-methylimidazole, pore size=12.0 Å);
MIL-88B, i.e., Cr ₃ OF(BDC) ₃ (pore size=15.6 Å);
MIL-88C, i.e. Fe ₃ O(NDC) ₃ (NDC=2,6-naphthalenedicarboxylate, pore size=18.7 Å);
MIL-88D, i.e., Cr ₃ OF(BPDC) ₃ (BPDC=4,4′-biphenyldicarboxylate, pore size=20.5 Å);
CID-1, i.e., Zn ₂ (ip) ₂ (bpy) ₂ (ip=isophthalate, bpy=4,4′-bipyridine, pore size=5.0 Å);
ZrO (BPCD) (pore diameter = 6.4 Å),
Al(OH)(NDC) (pore size = 8.5 Å).

The porous metal complex is preferably at least one selected from the group consisting of Zn ₂ (1,4-benzenedicarboxylate) ₂ triethylenediamine and Zn ₂ (1,4-naphthalenedicarboxylate) ₂ triethylenediamine, and more preferably Zn ₂ (1,4-benzenedicarboxylate) ₂ triethylenediamine or Zn ₂ (1,4-naphthalenedicarboxylate) ₂ triethylenediamine.

The porous metal complexes can be produced by known methods (e.g., the method described in Chun, H. et al., Chem. Eur. J. 2005, 11, 3521-3529).

(Method for producing high purity branched polyethylene glycol compound)
The method for producing a high purity branched chain polyethylene glycol compound (hereinafter sometimes abbreviated as "branched chain PEG compound") of the present invention includes the steps of:
(1) a step of mixing a mixture containing a branched PEG compound and a linear polyethylene glycol compound (hereinafter sometimes abbreviated as "linear PEG compound") as an impurity with a porous metal complex in the presence or absence of a solvent to adsorb the linear PEG compound onto the porous metal complex;
(2a) is a step of removing the porous metal complex having the linear PEG compound adsorbed thereon from a mixture containing the porous metal complex having the linear PEG compound adsorbed thereon and the branched PEG compound, when the mixing in step (1) is carried out in the presence of a solvent, to obtain a solution containing the branched PEG compound; or (2b) is a step of mixing the mixture containing the porous metal complex having the linear PEG compound adsorbed thereon and the branched PEG compound with a solvent, to obtain a solution containing the branched PEG compound, when the mixing in step (1) is carried out in the absence of a solvent, to obtain a solution containing the branched PEG compound; and (3) is a step of recovering the branched PEG compound from the solution containing the branched PEG compound.
Includes.

<Step (1)>
The mixing in step (1) is carried out in the presence or absence of a solvent. In this specification, "step (1) in which mixing is carried out in the presence of a solvent" may be referred to as "step (1a)", and "step (1) in which mixing is carried out in the absence of a solvent" may be referred to as "step (1b)".

The amount of the porous metal complex used in step (1a) or step (1b) is preferably 15 to 105 parts by mass, more preferably 25 to 95 parts by mass, per 100 parts by mass of the branched PEG compound, from the viewpoints of operability and separability.

Step (1) is preferably step (1a). Therefore, the production method of the present invention preferably includes steps (1a), (2a), and (3). The solvent used in step (1a) is preferably at least one selected from the group consisting of N,N-dimethylformamide (DMF), ethanol, ethyl acetate, chloroform, and toluene, and more preferably DMF or toluene.

The amount of the solvent used in step (1a) is preferably 250 to 400 parts by mass, more preferably 300 to 360 parts by mass, per 100 parts by mass of the branched PEG compound, from the viewpoint of the viscosity of the mixture in step (1).

The mixing temperature in step (1a) or step (1b) is preferably 25 to 150°C, more preferably 60 to 100°C, and the mixing time is preferably 1 to 24 hours, more preferably 2 to 8 hours.

The mixing in step (1a) or step (1b) may be carried out in an air atmosphere or in an inert atmosphere (e.g., a nitrogen atmosphere). From the viewpoint of simplicity, it is preferable to carry out the mixing in step (1a) or step (1b) in an air atmosphere.

<Step (2a) or Step (2b)>
Step (1a) is followed by step (2a), and step (1b) is followed by step (2b).

A solvent may be added to the mixture obtained in step (1a), and the mixture thus obtained (i.e., a dilution product) may be used in step (2a). The solvent is at least one selected from the group consisting of N,N-dimethylformamide (DMF), ethanol, ethyl acetate, chloroform, and toluene, and is more preferably DMF, chloroform, or toluene. From the viewpoint of the viscosity of the dilution product, the amount of the solvent used is preferably 500 to 2000 parts by mass, more preferably 1000 to 1400 parts by mass, per 100 parts by mass of the branched PEG compound.

In step (2a), the porous metal complexes having adsorbed linear PEG compounds are removed from a mixture containing the porous metal complexes having adsorbed linear PEG compounds and the branched PEG compounds (e.g., the mixture obtained in step (1a) or a dilution thereof) to obtain a solution containing the branched PEG compounds.

In step (2b), a mixture containing the porous metal complex having the linear PEG compound adsorbed thereon and the branched PEG compound is mixed with a solvent, and the porous metal complex having the linear PEG compound adsorbed thereon is removed from the mixture thus obtained to obtain a solution containing the branched PEG compound.

The solvent used in step (2b) is preferably at least one selected from the group consisting of N,N-dimethylformamide (DMF), ethanol, ethyl acetate, chloroform, and toluene, and more preferably chloroform. The amount of the solvent used in step (2b) is preferably 1,000 to 1,200 parts by mass, more preferably 800 to 1,000 parts by mass, per 100 parts by mass of the branched PEG compound, from the viewpoint of the viscosity of the mixture in step (2b).

In step (2b), the temperature at which the mixture containing the porous metal complex adsorbing the linear PEG compound and the branched PEG compound is mixed with the solvent is preferably 20 to 50°C, more preferably 25 to 45°C, and the mixing time is preferably 5 to 30 minutes, more preferably 10 to 20 minutes.

The mixing in step (2b) may be carried out in an air atmosphere or in an inert atmosphere (e.g., a nitrogen atmosphere). From the viewpoint of simplicity, it is preferable that the mixing in step (2b) is carried out in an air atmosphere.

In step (2a) or step (2b), there is no particular limitation on the means for removing the porous metal complex to which the linear PEG compound is adsorbed, and the porous metal complex can be removed by known means (e.g., filtration or centrifugation).

<Step (3)>
In step (3), the branched PEG compound is recovered from the solution containing the branched PEG compound. The means for recovering the branched PEG compound is not particularly limited, and the branched PEG compound can be recovered by a known means (e.g., solid-liquid separation by distilling off the solvent or adding a poor solvent).

When the solvent is distilled off from a solution containing a branched PEG compound, the temperature is preferably 20 to 60°C, more preferably 35 to 45°C, the pressure is preferably 2 to 20 kPa, more preferably 5 to 15 kPa, and the time is preferably 0.5 to 4 hours, more preferably 1 to 2 hours.

The poor solvent for solid-liquid separation is preferably at least one selected from the group consisting of n-hexane, diethyl ether, and methyl tert-butyl ether, more preferably n-hexane. The amount of the poor solvent used is preferably 100 to 200 parts by mass, more preferably 120 to 180 parts by mass, per 100 parts by mass of the solvent in the solution containing the branched PEG compound. The temperature at which the poor solvent is added to the solution containing the branched PEG compound is preferably 25 to 45°C, more preferably 30 to 40°C.

The solid containing the branched PEG compound precipitated by the addition of the poor solvent can be recovered by known means (e.g., filtration or centrifugation).

The mixture containing a branched PEG compound and a linear PEG compound used in step (1a) or (1b) is preferably obtained by the following steps (P1) and (P2). That is, the production method of the present invention preferably includes steps (P1), (P2), (1a), (2a), and (3), or includes steps (P1), (P2), (1b), (2b), and (3), and more preferably includes steps (P1), (P2), (1a), (2a), and (3).

<Step (P1)>
The step (P1) is a step of alcoholating a part of a polyol compound represented by any one of the following formulas (iia) to (iic) (hereinafter sometimes abbreviated as "polyol compound").

The reactant for alcoholating the polyol compound is preferably an alkali metal salt such as sodium methoxide or potassium hydroxide. The amount of the reactant (preferably an alkali metal salt) used relative to the polyol compound is preferably 5 to 50 mol %, more preferably 15 to 40 mol %, from the viewpoint of the rate of addition polymerization of ethylene oxide in step (P2). Here, "the amount of reactant used relative to the polyol compound" means "100 x amount of reactant (mol) / amount of polyol compound (mol)".

If the amount of reactant (preferably an alkali metal salt) used for the polyol compound in step (P1) is less than 5 mol%, the rate of addition polymerization of ethylene oxide in step (P2) slows down, increasing the thermal history and generating impurities such as terminal vinyl ethers. For this reason, it is advantageous to set the amount to 5 mol% or more in order to produce a high-quality high molecular weight product. Also, if the amount used exceeds 50 mol%, the viscosity of the reaction mixture increases or it solidifies during the alcoholation reaction, reducing the stirring efficiency and tending not to promote alcoholation.

The reaction temperature between the polyol compound and the reactant (preferably an alkali metal salt) is preferably 10 to 50°C, more preferably 20 to 40°C. If the reaction temperature is higher than 50°C, a decomposition reaction of the polyol compound occurs, producing low molecular weight impurities. If the reaction temperature is lower than 10°C, the reaction mixture tends to become viscous or solidify, making it difficult to handle.

The reaction time for the alcoholation in step (P1) is preferably 1 to 24 hours, more preferably 6 to 18 hours. If the reaction time is shorter than 1 hour, the alcoholation reaction may not proceed sufficiently. If the reaction time is longer than 24 hours, a decomposition reaction of the polyol compound may occur.

The alcoholation reaction in step (P1) is preferably carried out in the presence of an aprotic solvent. Examples of aprotic solvents include toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, methylene chloride, dimethyl sulfoxide, N,N-dimethylformamide, and dimethylacetamide. Only one aprotic solvent may be used, or two or more may be used in combination. Toluene is preferred as the aprotic solvent. The alcoholation reaction in step (P1) may be carried out in the absence of a solvent.

When an aprotic solvent is used, the amount used is preferably 1,000 to 3,000 parts by mass, and more preferably 1,500 to 2,500 parts by mass, per 100 parts by mass of the polyol compound.

In step (P1), in order to promote the alcoholation reaction, the alcoholation reaction is carried out while removing low molecular weight compounds produced in the alcoholation reaction (for example, methanol produced by the reaction of a polyol compound with sodium methoxide, or water produced by the reaction of a polyol compound with potassium hydroxide) under reduced pressure. Therefore, the pressure during the alcoholation reaction is preferably 5 to 35 kPa, more preferably 10 to 30 kPa.

In step (P1), a mixture containing a polyol compound and an alcoholate (hereinafter referred to as the "mixture of step (P1)") is obtained.

<Step (P2)>
Step (P2) is a step of carrying out addition polymerization of ethylene oxide. More specifically, step (P2) is a step of carrying out addition polymerization by supplying ethylene oxide to the mixture of step (P1). From the viewpoints of reaction pressure and safety, the supply rate of ethylene oxide (g/h/mol) is preferably 50 to 250 g/h/mol, more preferably 100 to 200 g/h/mol. The "supply rate of ethylene oxide (g/h/mol)" means the supply amount (g) of ethylene oxide per mol of the total of the polyol compound and the alcoholate and per hour.

The temperature for the addition polymerization of ethylene oxide is preferably 50 to 130°C, more preferably 60 to 120°C. If the temperature is lower than 50°C, the rate of addition polymerization is slow and the thermal history increases, tending to reduce the quality of the resulting branched PEG compound. If the temperature is higher than 130°C, side reactions such as vinyl etherification of the terminals occur during the addition polymerization, tending to reduce the quality of the resulting branched PEG compound. There is no particular limit to the time for addition polymerization, and it is sufficient to carry out addition polymerization until a branched PEG compound having the desired molecular weight is obtained.

The addition polymerization of ethylene oxide is preferably carried out in the presence of an aprotic solvent. Examples of aprotic solvents include toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, methylene chloride, dimethylsulfoxide, N,N-dimethylformamide, and dimethylacetamide. Only one aprotic solvent may be used, or two or more may be used in combination. Toluene is a preferred aprotic solvent.

When an aprotic solvent is used, the amount used is preferably 200 to 1800 parts by mass, more preferably 500 to 1500 parts by mass, per 100 parts by mass of the mixture in step (P1).

After the addition polymerization in step (P2), it is preferable to treat the reaction mixture with an acid such as phosphoric acid. By such an acid treatment, a mixture (hereinafter abbreviated as "mixture of step (P2)") containing a branched PEG compound, compound (I) in which m in formula (I) is 0, s is 3 to 5, s n's are both numbers from 20 to 2000, s X's are hydroxyl groups, and E is a linker represented by any one of formulas (IIa) to (IIc), and a linear PEG compound as an impurity is obtained.

When the addition polymerization of ethylene oxide in step (P2) is carried out in the presence of an aprotic solvent, the mixture of step (P2) can be recovered from a solution containing the mixture of step (P2), and the obtained mixture can be used to carry out step (1) (i.e., step (1a) or step (1b)). There are no particular limitations on the means for this recovery, and the mixture of step (P2) can be recovered by known means (e.g., solid-liquid separation by distilling off the solvent or adding a poor solvent).

When the solvent is distilled off from the solution containing the mixture in step (P2), the temperature is preferably 30 to 70°C, more preferably 40 to 60°C, the pressure is preferably 2 to 20 kPa, more preferably 5 to 15 kPa, and the time is preferably 0.5 to 4 hours, more preferably 1 to 2 hours.

The poor solvent for solid-liquid separation is preferably at least one selected from the group consisting of n-hexane, diethyl ether, and methyl tert-butyl ether, more preferably n-hexane. The amount of poor solvent used is preferably 500 to 3000 parts by mass, more preferably 1000 to 3000 parts by mass, per 100 parts by mass of the solvent in the solution containing the mixture of step (P2). The temperature at which the poor solvent is added to the solution containing the mixture of step (P2) is preferably 25 to 45°C, more preferably 30 to 40°C.

The mixture of step (P2) can be used to carry out step (1) (i.e., step (1a) or step (1b)). That is, in step (1), the mixture of step (P2) and a porous metal can be mixed in the presence or absence of a solvent, thereby allowing the linear PEG compound to be adsorbed onto the porous metal complex.

When the addition polymerization of ethylene oxide in step (P2) is carried out in the presence of an aprotic solvent, the solution containing the mixture of step (P2) obtained can be used to carry out step (1a). That is, in step (1a), the solution containing the mixture of step (P2) is mixed with a porous metal, so that the linear PEG compound can be adsorbed onto the porous metal complex.

The present invention will be explained in more detail below based on examples. Note that the present invention is not limited to the embodiments of the examples.

In the examples, the following porous metal complexes were used:
MOF (1): Zn _{2 (} 1,4-benzenedicarboxylate) ₂ triethylenediamine (pore size: 0.75 nm ₎ ("AP3025" manufactured by Atomis Corporation)
MOF (2): Zn _{2 (} 1,4-naphthalenedicarboxylate) ₂ triethylenediamine (pore size: 0.57 nm ₎ (prepared by the method described in Nature Communication (2018) 9; 3635)
The pore sizes of MOF (1) and MOF (2) were measured by a nitrogen gas adsorption method.

Hereinafter, "polyethylene glycol" may be abbreviated as "PEG."
In the following Examples 1 to 9, the term "PEG mixture" refers to a mixture containing a branched PEG compound and a linear PEG compound that have not been treated with a porous metal complex, and does not include a solvent.
In the following Examples 1 to 9, "main fraction purity" means the purity of the branched PEG compound, and "linear PEG content" means the content of the linear PEG compound.

In the following Comparative Example 1, the term "PEG mixture" refers to a mixture containing a high molecular weight branched PEG compound having an Mn of 40,000 and a low molecular weight branched PEG compound having an Mn of 20,000 that has not been treated with a porous metal complex. The PEG mixture does not contain a solvent.
In the following Comparative Example 1, "main fraction purity" means the purity of the high molecular weight branched PEG compound, and "low molecular weight PEG content" means the content of the low molecular weight branched PEG compound.

(Evaluation Method)
(i) Mn of the PEG compounds used in the following Examples 1 to 9 and Comparative Example 1, and (ii) the main fraction purity, linear PEG content (or low molecular weight PEG content), and polydispersity (hereinafter abbreviated as "Mw/Mn") of the raw materials (PEG mixtures) and the target products obtained in the following Examples 1 to 7 and 9 and Comparative Example 1 were calculated by gel permeation chromatography (GPC) measurement (standard: polyethylene glycol) under the following conditions. Note that the Mw/Mn of the raw materials (PEG mixtures) and the target products obtained in Example 8 was not calculated.
<GPC measurement conditions>
Equipment: Shimadzu Corporation "Prominence"
Detector: RI
Column: PLgel 5 μm MIXED-D 300 × 7.5 mm (2 columns connected)
Mobile phase: N,N-dimethylformamide Flow rate: 0.7 mL/min

The purity of the main fraction and the linear PEG content of the raw material (PEG mixture) used in Example 8 and the target product obtained were calculated by derivatizing the hydroxyl groups at the ends of the PEG with 3,5-dinitrobenzoyl chloride and then carrying out reversed-phase high performance liquid chromatography (RP-HPLC) measurement under the following conditions.
<RP-HPLC measurement conditions>
Apparatus: "Alliance" manufactured by Waters Corporation
Detector: UV (210 nm)
Column: Zorbax 300SB-C18 (3.0 x 150 mm)
Mobile phase A: water Mobile phase B: acetonitrile Flow rate: 0.6 mL/min
Gradient conditions: as shown in Table 1.

Example 1
A PEG mixture (main fraction purity = 95.98%, linear PEG content = 3.32 mass%, Mw / Mn = 1.033, 0.3 g) containing a branched PEG compound represented by the following formula (III) (Mn = 41,223) and a linear PEG compound represented by the following formula (IV) (Mn = 20,857) and MOF (2) (0.1 g) were weighed into a glass flask and mixed with N,N-dimethylformamide (DMF) (0.9 g). The mixture was stirred at 80 ° C. for 5 hours, cooled, diluted with chloroform (3 g), and separated into MOF (2) and a solution containing branched PEG by centrifugation. The solvent of the obtained solution was distilled off for 1 hour under conditions of temperature: 40 ° C. and pressure: 10 KPa to obtain the target product. The purity of the main fraction of the target product was 97.04%, the linear PEG content was 2.36% by mass, and Mw/Mn was 1.029.

Example 2
A PEG mixture (main fraction purity = 88.05%, linear PEG content = 11.63% by mass, Mw / Mn = 1.068) containing a branched PEG compound represented by the above formula (III) (Mn = 40,376, main fraction purity = 99.33%, linear PEG content = 0% by mass, Mw / Mn = 1.024, 0.27 g) and a linear PEG compound represented by the following formula (V) (Mn = 20,598, 0.03 g) and MOF (2) (0.225 g) were weighed into a glass flask and mixed with N,N-dimethylformamide (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with chloroform (3 g), and centrifuged to separate MOF (2) and a solution containing the branched PEG compound. The solvent of the obtained solution was distilled off for 1 hour under conditions of a temperature of 40° C. and a pressure of 10 KPa to obtain the target product, which had a main fraction purity of 92.19%, a linear PEG content of 7.30% by mass, and an Mw/Mn of 1.051.

In Example 2, a PEG mixture was used that was obtained by adding a linear PEG compound represented by the above formula (V) to a branched PEG compound represented by the above formula (III). The terminal functional groups of both the branched PEG compound and the linear PEG compound are a hydroxyl group and a benzyloxy group, and the difference between these two PEG compounds is the branched or linear structure. Since the main fraction purity of the target product obtained by the method of Example 2 is improved compared to the main fraction purity of the PEG mixture, it can be seen that the manufacturing method of the present invention can remove linear PEG compounds from a PEG mixture and obtain a high purity branched PEG compound even if there is no difference in the terminal functional groups.

Example 3
A PEG mixture (main fraction purity = 87.74%, linear PEG content = 11.62 mass%, Mw / Mn = 1.042) containing a branched PEG compound represented by the following formula (VI) (Mn = 34,302, main fraction purity = 95.74%, linear PEG content = 3.32 mass%, Mw / Mn = 1.044, 0.27 g), and a linear PEG compound represented by the above formula (IV) (Mn = 21,172, 0.03 g) were weighed into a glass flask, and MOF (2) (0.225 g) was mixed with N,N-dimethylformamide (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with N,N-dimethylformamide (3 g), and filtered to separate the solution containing MOF (2) and branched PEG. To the obtained solution, n-hexane (6.0 g) was added at 35° C. to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the target product was 92.55%, the linear PEG content was 7.00% by mass, and Mw/Mn was 1.032.

In Example 3, a PEG mixture was used that was obtained by adding a linear PEG compound represented by the above formula (IV) to a branched PEG compound represented by the above formula (VI). The terminal functional groups of both the branched PEG compound and the linear PEG compound are hydroxy groups, and the difference between these two PEG compounds is the presence or absence of a branched structure and the molecular weight. Since the main fraction purity of the target product obtained by the method of Example 3 is improved compared to the main fraction purity of the PEG mixture, it can be seen that the manufacturing method of the present invention can remove linear PEG compounds from a PEG mixture and obtain a high purity branched PEG compound even without differences in terminal functional groups.

Example 4
The branched PEG compound represented by the formula (III) (Mn = 40,488, main fraction purity = 99.33%, linear PEG content = 0 mass%, Mw / Mn = 1.024, 0.27 g), and the linear PEG compound represented by the formula (IV) (Mn = 18,945, 0.03 g) were weighed into a glass flask, and MOF (1) (0.225 g) was mixed with toluene (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and the branched PEG. To the obtained solution, n-hexane (6.0 g) was added at 35° C. to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the obtained target product was 99.41%, the linear PEG content was 0 mass%, and Mw/Mn was 1.020.

Example 5
The branched PEG compound represented by the formula (III) (Mn = 19,774, main fraction purity = 98.27%, linear PEG content = 1.72% by mass, Mw / Mn = 1.038, 0.27 g), and the linear PEG compound represented by the formula (IV) (Mn = 9,943, 0.03 g) were weighed into a glass flask containing a PEG mixture (main fraction purity = 88.07%, linear PEG content = 11.93% by mass, Mw / Mn = 1.070), and MOF (1) (0.225 g) were mixed with toluene (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and branched PEG. To the obtained solution, n-hexane (6.0 g) was added at 35° C. to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the obtained target product was 98.95%, the linear PEG content was 0 mass%, and Mw/Mn was 1.027.

Example 6
A PEG mixture (main fraction purity = 90.73%, linear PEG content = 9.37% by mass, Mw / Mn = 1.132) containing the branched PEG compound represented by the above formula (III) (Mn = 5,386, main fraction purity = 100.00%, linear PEG content = 0% by mass, Mw / Mn 1.021, 0.27 g), and a linear PEG compound represented by the above formula (IV) (Mn = 1,829, 0.03 g) were weighed into a glass flask, and MOF (1) (0.225 g) was mixed with toluene (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and the branched PEG. n-Hexane (6.0 g) was added to the obtained solution at 35 ° C. to precipitate the branched PEG compound. The precipitated solid was collected by filtration to obtain the target product, which had a main fraction purity of 100%, a linear PEG content of 0 mass%, and an Mw/Mn value of 1.021.

(Example 7)
A PEG mixture (main fraction purity = 90.11%, linear PEG content = 9.89% by mass, Mw / Mn = 1.108) containing the branched PEG compound represented by the formula (VII) (Mn = 4,689, main fraction purity = 100.00%, linear PEG content = 0% by mass, Mw / Mn 1.020, 0.27 g) and the linear PEG compound represented by the formula (IV) (Mn = 1,810, 0.03 g) was weighed into a glass flask and mixed with toluene (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled and diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and the branched PEG. n-Hexane (6.0 g) was added to the obtained solution at 35 ° C. to precipitate the branched PEG compound. The precipitated solid was collected by filtration to obtain the target product, which had a main fraction purity of 100%, a linear PEG content of 0 mass%, and an Mw/Mn value of 1.020.

(Example 8)
A PEG mixture (main fraction purity = 90.03%, linear PEG content = 9.97% by mass) containing the branched PEG compound represented by the formula (VI) (Mn = 18,091, main fraction purity = 97.30%, linear PEG content = 2.70% by mass, 0.27 g) and the linear PEG compound represented by the formula (IV) (Mn = 18,628, 0.03 g), as well as MOF (1) (0.225 g) were weighed into a glass flask and mixed with toluene (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled and diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and the branched PEG. To the obtained solution, n-hexane (6.0 g) was added at 35 ° C. to precipitate the branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The purity of the main fraction of the obtained target product was 95.93%, and the linear PEG content was 4.07% by mass.

In Example 8, a PEG mixture containing branched PEG compounds and linear PEG compounds having similar Mn was used. The main fraction purity of the target product obtained by the method of Example 8 is improved compared to the main fraction purity of the PEG mixture, which shows that the manufacturing method of the present invention can remove linear PEG compounds from a PEG mixture to obtain a high-purity branched PEG compound, even if the branched PEG compounds and linear PEG compounds contained in the PEG mixture have similar Mn.

(Example 9)
A PEG mixture (main fraction purity = 96.21%, linear PEG content = 3.33 mass%, Mw / Mn = 1.034, 0.1 g) containing a branched PEG compound represented by the above formula (III) (Mn = 40,971) and a linear PEG compound represented by the above formula (IV) (Mn = 20,487) and MOF (2) (0.085 g) were weighed and mixed in a glass flask. The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with chloroform (3 g), and separated into MOF (2) and a solution containing a branched PEG compound by centrifugation. The solvent of the obtained solution was distilled off for 1 hour under conditions of temperature: 40 ° C. and pressure: 10 KPa to obtain the target product. The main fraction purity of the obtained target product was 97.08%, the linear PEG content was 2.45 mass%, and Mw / Mn was 1.029.

(Comparative Example 1)
A PEG mixture (main fraction purity = 88.58%, low molecular weight PEG content = 10.81% by mass, Mw / Mn = 1.068) containing a branched PEG compound having a molecular weight represented by the above formula (III) (Mn = 40,551, main fraction purity = 95.98%, low molecular weight PEG content = 3.32% by mass, Mw / Mn = 1.033, 0.27 g) and a branched PEG compound having a molecular weight represented by the above formula (III) (Mn = 20,124, 0.03 g) was weighed into a glass flask, and MOF (2) (0.225 g) was mixed with N,N-dimethylformamide (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with N,N-dimethylformamide (3 g), and filtered to separate the solution containing MOF (2) and branched PEG. To the obtained solution, n-hexane (6.0 g) was added at 35° C. to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the obtained target product was 88.87%, the low molecular weight PEG content was 10.84% by mass, and Mw/Mn was 1.067.

In Comparative Example 1, a PEG mixture was used that was obtained by adding a branched PEG compound represented by the above formula (III) with a different molecular weight to the branched PEG compound represented by the above formula (III). Both of these PEG compounds have a branched structure, and the difference between them is their molecular weight. Since the main fraction purity of the target product obtained by the method of Comparative Example 1 was not improved compared to the main fraction purity of the PEG mixture, it is clear that the PEG compound with a branched structure cannot sufficiently remove the PEG compounds with branched structures and different molecular weights, and a branched PEG compound with high purity cannot be obtained.

Table 2 below lists the branched PEG compound, linear PEG compound (low molecular weight branched PEG compound in Comparative Example 1), porous metal complex used (referred to as "MOF" in Table 2), solvent used in step (1a) (referred to as "solvent" in Table 2), mixing temperature in step (1a) or step (1b) (referred to as "mixing temperature" in Table 2), means for removing the porous metal complex (referred to as "MOF removal" in Table 2), main fraction purity and Mw/Mn of the PEG mixture, and main fraction purity and Mw/Mn of the target product used in Examples 1 to 9 or Comparative Example 1. Note that in Example 8, the Mw/Mn of the PEG mixture and the Mw/Mn of the target product were not calculated.

According to the present invention, a high-purity branched polyethylene glycol compound can be obtained. Such a high-purity branched polyethylene glycol compound can be used, for example, for medical purposes.

This application is based on patent application No. 2023-169554 filed in Japan, the contents of which are incorporated in their entirety into this specification.

Claims (10)

A method for producing a high purity branched polyethylene glycol compound, comprising the steps of:
a step (1a) of mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the presence of a solvent to adsorb the linear polyethylene glycol compound onto the porous metal complex;
a step (2a) of removing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon from a mixture containing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon and the branched polyethylene glycol compound to obtain a solution containing the branched polyethylene glycol compound; and a step (3) of recovering the branched polyethylene glycol compound from the solution containing the branched polyethylene glycol compound.
A manufacturing method comprising: A method for producing a high purity branched polyethylene glycol compound, comprising the steps of:
a step (1b) of mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the absence of a solvent to adsorb the linear polyethylene glycol compound onto the porous metal complex;
a step (2b) of mixing a mixture containing a porous metal complex having adsorbed thereon a linear polyethylene glycol compound and a branched polyethylene glycol compound with a solvent, and removing the porous metal complex having adsorbed thereon the linear polyethylene glycol compound from the mixture thus obtained to obtain a solution containing the branched polyethylene glycol compound; and a step (3) of recovering the branched polyethylene glycol compound from the solution containing the branched polyethylene glycol compound.
A manufacturing method comprising: The branched polyethylene glycol compound has the formula (I):
(In the formula, m is 0 or 1,
When m is 0, s is an integer from 3 to 9, and when m is 1, s is an integer from 2 to 8;
Each of the s n's is independently a number from 20 to 2000;
Y and the s number of X's are each independently a hydroxy group which may be substituted with a substituent, and E is a linker having a valency of (s+m).
The method according to claim 1 or 2, wherein the branched compound is represented by the formula: The method according to claim 3, wherein the substituent is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an isoheptyl group, a phenyl group, a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group. The method of claim 3, wherein E is a linker having a structure obtained by removing a hydroxy group from glycerin, diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, pentaerythritol, dipentaerythritol, tetritol, pentitol, or hexitol. The method according to claim 1 or 2, wherein the solvent used in step (1a) or step (2b) is at least one selected from the group consisting of N,N-dimethylformamide, ethanol, ethyl acetate, chloroform, and toluene. The method according to claim 1 or 2, wherein the number average molecular weight of the branched polyethylene glycol compound is 4,000 to 80,000. The method according to claim 1 or 2, wherein the number average molecular weight of the branched polyethylene glycol compound is 5,000 to 80,000. The method according to claim 1 or 2, wherein the number average molecular weight of the linear polyethylene glycol compound is 1,500 to 90,000. The method according to claim 1 or 2, wherein the number average molecular weight of the linear polyethylene glycol compound is 2,000 to 90,000.